The ability of rod-mediated vision to detect absorption of a handful of photons has led to a set of pre-cise questions about how single photon absorptions are transduced and processed in the retina. These questions have led to a series of breakthroughs in our understanding of the biophysical basis of rod vision, and more generally of the fidelity of neural processing. The behavioral performance of cone vision is similarly impressive, but its relation to biophysical mechanisms is much less clear. This gap in our understanding limits how strongly behavioral results constrain retinal processing of cone-mediated signals. The broad goal of the work proposed here is to elucidate how biophysical mechanisms operating in the rod and cone photoreceptors and the associated retinal circuits enhance and limit visual fidelity. We will focus on three sets of questions: (1) How is rhodopsin's active lifetime controlled to generate single photon responses with low trial-to-trial variability? (2) What sources of noise limit the fidelity of the retinal outputs at low light levels? (3) What is the origin of noise in the responses of cone photoreceptors and what is its impact on the fidelity of the retinal output? We will answer these questions through a combination of electrophysiological recordings of responses in mouse and primate retina and genetic manipulations in mouse retina. Similar issues arise in many other neural circuits; thus the proposed work will improve our general understanding of neural function. PUBLIC HEALTH RELEVANCE: The ability of rod photoreceptors to detect single photons has helped make rod phototransduction the best understood of the many G-protein cascades in biological systems. It also has had direct medical benefits, as we now understand the mechanisms and have potential treatments for several forms of stationary night blindness. We know much less about the retinal readout of rod signals and the generation and processing of cone signals. The long-term aim of the work described here is to help fill this gap in our knowledge. As we have in the past, we will use the technical and conceptual progress made in this work to test transgenic models for visual deficits.